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Timmerbeul, Inke; Garrett-Engele, Carrie M.; Kossatz, Uta; Chen, Xueyan; Firpo, Eduardo; Grünwald, Viktor; Kamino, Kenji; Wilkens, Ludwig; Lehmann, Ulrich; Buer, Jan; Geffers, Robert; Kubicka, Stefan; Manns, Michael P.; Porter, Peggy L.; Roberts, James M.; Malek, Nisar P.

Testing the Importance of p27 Degradation by the$SCF^{skp2}$Pathway in Murine Models of Lung and Colon Cancer

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  • Media type: E-Article
  • Title: Testing the Importance of p27 Degradation by the$SCF^{skp2}$Pathway in Murine Models of Lung and Colon Cancer
  • Contributor: Timmerbeul, Inke; Garrett-Engele, Carrie M.; Kossatz, Uta; Chen, Xueyan; Firpo, Eduardo; Grünwald, Viktor; Kamino, Kenji; Wilkens, Ludwig; Lehmann, Ulrich; Buer, Jan; Geffers, Robert; Kubicka, Stefan; Manns, Michael P.; Porter, Peggy L.; Roberts, James M.; Malek, Nisar P.
  • imprint: National Academy of Sciences, 2006
  • Published in: Proceedings of the National Academy of Sciences of the United States of America
  • Language: English
  • ISSN: 0027-8424
  • Origination:
  • Footnote:
  • Description: <p>Decreased expression of the CDK inhibitor<tex-math>$p27_{kip1}$</tex-math>in human tumors directly correlates with increased resistance to chemotherapies, increased rates of metastasis, and an overall increased rate of patient mortality. It is thought that decreased p27 expression in tumors is caused by increased proteasomal turnover, in particular activation of the pathway governed by the<tex-math>$SCF^{skp2}$</tex-math>E3 ubiquitin protein ligase. We have directly tested the importance of the<tex-math>$SCF^{skp}$</tex-math>-mediated degradation of p27 in tumorigenesis by analyzing the tumor susceptibility of mice that express a form of p27 that cannot be ubiquitinated and degraded by this pathway (p27T187A). In mouse models of both lung and colon cancer down-regulation of p27 promotes tumorigenesis. However, we found that preventing p27 degradation by the<tex-math>$SCF^{skp2}$</tex-math>pathway had no impact on tumor incidence or overall survival in either tumor model. Our study unveiled a previously unrecognized role for the control of p27 mRNA abundance in the development of non-small cell lung cancers. In the colon cancer model, the frequency of intestinal adenomas was similarly unaffected by the p27T187A mutation, but, unexpectedly, we found that it inhibited progression of intestinal adenomas to carcinomas. These studies may guide the choice of clinical settings in which pharmacologic inhibitors of the Skp2 pathway might be of therapeutic value.</p>
  • Access State: Open Access